The goal of this research project is to evaluate the role of the cholinergic system in the mood, behavioral and cognitive symptoms observed in mood disorders in humans, using clinical assessment, computerized cognitive testing and functional brain neuroimaging techniques. In addition to pervasive sadness, specific aspects of behavior and cognition are impaired in mood disorders, including selective attention, set-shifting and memory; and there also is evidence that depressed individuals exhibit a mood congruent processing bias whereby they more readily process negatively toned information as compared to positively toned information. This cognitive pattern lends itself to evaluation with functional brain imaging, both in terms of identifying the anatomical correlates of the specific behavioral and cognitive differences as well as characterizing the effects of pharmacological manipulation. Attention and memory functions are closely tied to the cholinergic neurotransmitter system whereby drugs that enhance cholinergic function are found to enhance memory and attention while agents that interfere with normal cholinergic function impair performance on attention and memory tasks. Moreover, the cholinergic system is one of the neurotransmitter systems implicated in the pathophysiology of mood disorders. Evidence suggests that during major depressive episodes, the cholinergic system is hypersensitive to acetylcholine. Agents that enhance muscarinic cholinergic receptor function increase depressive symptoms in depressed subjects, and can produce symptoms of depression in healthy subjects. The preclinical literature more specifically implicates the muscarinic receptors and indicates that the use of muscarinic antagonists, in the context of animal models of depression, results in improvement in the behavioral analogs of depression. This on-going project investigates the role of cholinergic neurotransmission in the mood, behavioral and cognitive symptoms observed in the depressed phase of both major depressive disorder (MDD) and bipolar disorder (BD). The studies proposed here will identify anatomical correlates of the mood congruent processing bias, working memory, attention and set-shifting deficits observed in depressed subjects. Further, these studies will evaluate the effects of the cholinergic antagonist, scopolamine, on mood in patient populations, and on the performance deficits and neural activity in brain regions recruited as subjects perform these cognitive tasks. This approach is expected to reveal how neuromodulators influence processing in brain structures recruited to perform these tasks, both in healthy individuals and in major depressive disorders. The combined use of functional brain imaging and pharmacological manipulation to evaluate the role of neurotransmitter dysfunction in depression may direct us to potential therapeutic approaches. These studies also are expected to elucidate the role of cholinergic muscarinic receptors in the mood and cognitive symptoms observed in depression. To date we have found that in healthy individuals, scopolamine modulates performance on attention tasks but does so differentially based on the emotional content of the stimuli with greater effects associated with sad stimuli. This result suggests that manipulation of cholinergic function in healthy individuals modulates the salience of emotional stimuli. We also are beginning to uncover baseline performance differences between the healthy and depressed groups that indicate differential processing of emotional stimuli, which is a potentially important finding as the development of tasks that reliably distinguish between healthy individuals and depressed patients has proven to be extremely difficult. Moreover, we have found evidence that scopolamine modulates performance differentially in healthy and depressed individuals based on the emotional content of the stimuli, supporting the hypothesis that acetylcholine is processing emotional stimuli differently in patients with mood disorders. As predicted, performance is actually improved during scopolamine in patients for some components of the task, while in healthy individuals only performance decrements are observed. This prediction was based on the hypothesis that the over-activity of the cholinergic system in depression results in an enhanced perceptual representation of negative stimuli that interfered with task performance, and that blocking overactive muscarinic receptors will diminish this effect. Finally, we have preliminary findings showing both baseline performance differences and differential responses to scopolamine between the MDD and BD groups, differences that again are based on the emotional content of stimuli. As the identification of performance differences between these patient groups has been elusive, this finding also has the potential to be very revealing. The behavioral findings have guided functional imaging studies designed to elucidate the neurophysiological basis for observed differences between healthy individuals and patient groups, and for the differential responses to scopolamine. In healthy individuals, a bias towards faces that is evident during placebo is diminished during scopolamine. These effects are consistent with selective reductions in the fMRI BOLD signal in the lateral fusiform cortical region (face fusiform cortex) and in the amygdala, a region known to respond to faces and to respond differentially to facial expressions of emotion. We also have begun to assess differences in the effects of scopolamine on BOLD response to facial expressions in healthy individuals, and have observed selective effects on responses in lateral fusiform cortex and in amygdala as emotion is modulated in faces despite the fact that the emotional content is irrelevant to task performance requirements. These preliminary results may suggest that an inherent bias towards faces is modulated preferentially by scopolamine, and that the influence of cholinergic modulation differs based on the emotion content. Results from healthy subjects currently are being submitted The most important finding to date in the context of this project is that we have observed rapid and robust anti-depressant responses to scopolamine in our patient groups. Following a clinical observation (in the context of cognitive studies) that our patient groups showed antidepressant responses to scopolamine, we designed and completed a treatment study in a group of MDD and BD patients, the results of which have confirmed that scopolamine is having a dramatic antidepressant effect. We observed antidepressant responses that were clinically significant by the next clinic visit (generally 3 days later) following a single i.v. administration of scopolamine, and by patient report the effect actually was faster. Moreover, over 55% of our patients, the majority of whom were treatment resistant, experienced remission of symptoms. In our estimation, scopolamine has the potential to become a new option for the clinical treatment of depression in MDD and BD. Follow-up studies designed to evaluate the efficacy of other routes of administration of scopolamine in patient groups currently are under IRB review. Follow-up analyses have revealed that the effectiveness of scopolamine is comparable in currently depressed unipolar and bipolar patients, while the effect is significantly larger in females than in males. Clinical findings currently are in press in the Archives of General Psychiatry. Behavioral results detailing the selective effects of scopolamine on performance during an attention task with emotion modulation in healthy adults is ready for submission. Aspects of these results have been presented at Biological Psychiatry, the American College of Neuropsychopharmacology and Human Brain Mappping.